VATICAN (Ventilator-Associated Tracheobronchitis Initiative to Conduct Antibiotic Evaluation): protocol for a multicenter randomized open-label trial of watchful waiting versus antimicrobial therapy for ventilator-associated tracheobronchitis

ABSTRACT Background Ventilator-associated tracheobronchitis is a common condition among invasively ventilated patients in intensive care units, for which the best treatment strategy is currently unknown. We designed the VATICAN (Ventilator-Associated Tracheobronchitis Initiative to Conduct Antibiotic Evaluation) trial to assess whether a watchful waiting antibiotic treatment strategy is noninferior to routine antibiotic treatment for ventilator-associated tracheobronchitis regarding days free of mechanical ventilation. Methods VATICAN is a randomized, controlled, open-label, multicenter noninferiority trial. Patients with suspected ventilator-associated tracheobronchitis without evidence of ventilator-associated pneumonia or hemodynamic instability due to probable infection will be assigned to either a watchful waiting strategy, without antimicrobial administration for ventilator-associated tracheobronchitis and prescription of antimicrobials only in cases of ventilator-associated pneumonia, sepsis or septic shock, or another infectious diagnosis, or to a routine antimicrobial treatment strategy for seven days. The primary outcome will be mechanical ventilation-free days at 28 days, and a key secondary outcome will be ventilator-associated pneumonia-free survival. Through an intention-to-treat framework with a per-protocol sensitivity analysis, the primary outcome analysis will address noninferiority with a 20% margin, which translates to a 1.5 difference in ventilator-free days. Other analyses will follow a superiority analysis framework. Conclusion The VATICAN trial will follow all national and international ethical standards. We aim to publish the trial in a high-visibility general journal and present it at critical care and infectious disease conferences for dissemination. These results will likely be immediately applicable to the bedside upon trial completion and will provide information with a low risk of bias for guideline development.


Ventilator-free days definition
Ventilator-free days (VFD) is defined as being free of invasive mechanical ventilation for at least 48 hours (successful extubation). (1)If the patient is reintubated within 48 hours of this time period be considered as zero VFDs.If reintubated 48 hours, this period will be counted as VFDs.Patients who undergo a tracheostomy will be considered free of mechanical ventilation once they tolerate continuous nebulization (with or without oxygen), allowing for short periods (< 1 hour) of positive pressure ventilation.Patients who are discharged alive before 28 days will be considered alive and free of mechanical ventilation at 28 days.Non-survivors up to 28 days will be considered as having zero VFDs.

Ventilator-associated pneumonia-free survival definition
Ventilator-associated pneumonia (VAP)-free survival is defined as the time between the patient's entry into the study and the diagnostic event of VAP or death.All patients will be censored within 28 days or upon hospital discharge, whichever comes first.

Intensive care unit-free days definition
Intensive care unit (ICU)-free days is defined as being alive and free of the ICU for at least 24 hours.Patients who are discharged alive before 28 days will be considered alive and free of ICU at day 28.Non-survivors at 28 days will be considered as having zero ICU-free days.

Antibiotics-free days at 28 days
Antibiotics-free days will be defined as being alive and free of antibiotics for at least 24 hours.Patients who are discharged alive before 28 days will be considered alive and free of antibiotics at day 28.Non-survivors at 28 days will be considered as having zero antibiotics-free days.

Ventilator-associated pneumonia diagnosis
The diagnosis of VAP will follow the Agência Nacional de Vigilância Sanitária's (ANVISA) definitions. (2)In this trial, we will use both clinical and microbiological definitions of VAP according to the following criteria: Clinical ventilator-associated pneumonia

MULTIDRUG RESISTANT MICROORGANISM DEFINITION
The operational definition of multidrug resistant microorganisms is described below

Microorganism
Resistance profile

Acinetobacter baumannii
Resistant to carbapenems and/or polymyxins

Pseudomonas aeruginosa
Resistant to carbapenems and/or polymyxins Enterobacteriaceae to carbapenems and/or polymyxins (for Enterobacteriaceae naturally sensitive to polymyxins)

Staphylococcus aureus
Resistant to methicillin/oxacillin

CUT-OFFS FOR LOWER RESPIRATORY TRACT CULTURE RESULTS
The cut-offs for lower respiratory tract culture results are described below.

Cut-off
Endotracheal aspirate ≥ 10 6 colony-forming units/mL Bronchoalveolar lavage ≥ 10 4 colony-forming units/mL Protect brush specimen ≥ 10 3 colony-forming units/mL Semi-quantitative culture Moderate or high growth Crit Care Sci.2024;36:e20240029en antimicrobial therapy (for VAT and all possible infections that might occur during the study) during the study period.Infection adjudications will be blinded to the intervention group.Regarding effectiveness of antimicrobial therapy, each antimicrobial regimen will be classified as: • Appropriate: when at least one antimicrobial used to treat the infection has in vitro activity against the isolated pathogen and has adequate penetration in the infection site.
• Inappropriate: when the isolated pathogen has in vitro resistance to all antimicrobials used for treating the infection or has inadequate penetration in the infection site.
• Indeterminate: when there is no pathogen isolated for that specific infection or the antibiotics used were not evaluated in the antibiogram.
All possible infections that might occur in both groups are evaluated.Adjudicators use a combination of data inserted on the eCRF, together with copies of medical records, radiology exams, and microbiological cultures results.Additional information might be requested to each site center if needed.For diagnosis of VAP we will follow the ANVISA's definitions as previously described.Other possible infections will be classified as suggested by Klein Klouwenberg et al.: (3) • Not infected: no clinical, laboratory or microbiological findings that suggest an infection or a definitive alternative explanation for clinical and laboratory findings.
• Possible infection: either all necessary information needed for a precise classification is not present in the medical records and other files evaluated or subtle physiological changes that might suggest inflammation but without microbiological confirmation.
• Probable or confirmed infection: unequivocal evidence of signs of infection, sepsis or septic shock, regardless of microbiological cultures, or infections with microbiological confirmation in sterile sites (confirmed) or non-sterile sites (probable) associated with evidence of infection.
For patients presenting with two or more same infection diagnosis within 14 days, we will only consider the first episode.